Validation of the Clinical Use of GIScar, an Academic-developed Genomic Instability Score Predicting Sensitivity to Maintenance Olaparib for Ovarian Cancer
Authors: Raphaël Leman, Etienne Muller, Angelina Legros, Nicolas Goardon, Imène Chentli, Alexandre Atkinson, Aurore Tranchant, Laurent Castera, Sophie Krieger, Agathe Ricou, Flavie Boulouard, Florence Joly, Romain Boucly, Aurélie Dumont, Noémie Basset, Florence Coulet, Louise-Marie Chevalier, Etienne Rouleau, Katharina Leitner, Antonio González-Martin, Piera Gargiulo, Hans-Joachim Lück, Catherine Genestie, Gerhard Bogner, Christian Marth, Edgar Petru, Alexander Reinthaller, Christian Schauer, Paul Sevelda, Lionel D'Hondt, Ignace Vergote, Peter Vuylsteke, Sakari Hietanen, Gabriel Lindahl, Johanna Mäenpää, Trine Jakobi Nøttrup, Ulla Puistola, Sophie Abadie-Lacourtoisie, Jérôme Alexandre, Emilie Boissier, Hugues Bourgeois, Annick Chevalier-Place, Pierre Combe, Cristina Costan, Jérôme Dauba, Laure De Cock, Christophe Desauw, Raymond Despax, Nadine Dohollou, Coraline Dubot, Michel Fabbro, Laure Favier, Anne Floquet, Philippe Follana, Claire Garnier Tixidre, Georges Garnier, Laurence Gladieff, Julien Grenier, Cécile Guillemet, Anne-Claire Hardy-Bessard, Florence Joly, Elsa Kalbacher, Marie-Christine Kaminsky, Jean-Emmanuel Kurtz, Rémy Largillier, Claudia Lefeuvre-Plesse, Anne Lesoin, Charles-Briac Levache, Tifenn L'Haridon, Alain Lortholary, Jean-Pierre Lotz, Jérôme Meunier, Mirerille Mousseau, Marie-Ange Mouret-Reynier, Patricia Pautier, Thierry Petit, Magali Provansal, Eric Pujade-Lauraine, Nadia Raban, Isabelle Ray-Coquard, Manuel Rodrigues, Frédéric Selle, Robert Sverdlin, Youssef Tazi, Benoît You, Bahriye Aktas, Dirk Olaf Bauerschlag, Thomas Beck, Antje Belau, Holger Bronger, Stefan Buchholz, Paul Buderath, Alexander Burges, Ulrich Canzler, Nikolaus de Gregorio, Dominik Denschlag, Max Dieterich, Michael Eichbaum, Ahmed El-Balat, Günter Emons, Peter Fasching, Gabriele Feisel-Schwickardi, Matthias Frank, Michael Friedrich, Eva-Maria Grischke, Martina Gropp-Meier, Lars Hanker, Carla Hannig, Philipp Harter, Annette Hasenburg, Martin Hellriegel, Uwe Herwig, Martin Heubner, Joachim Hulde, Christian Jackisch, Matthias Kögel, Peter Krieger, Thorsten Kühn, Clemens Liebrich, Hans-Joachim Lück, Peter Mallmann, Frederik Marmé, Werner Meier, Voker Möbus, Omar Farag Mohamed, Carolin Nestle-Krämling, Tanja Neunhöffer, Gülten Oskay-Özcelik, Tjoung-Won Park-Simon, Beate Rautenberg, Daniel Rein, Wencke Ruhwedel, Ingo Runnebaum, Jacqueline Sagasser, Barbara Schmalfeldt, Andreas Schneeweiss, Andreas Schnelzer, Heinz Scholz, Jalid Sehouli, Antje Sperfeld, Annette Steckkönig, Hans-Georg Strauß, Oliver Tomé, Jörn Treustedt, Hermann Voß, Arthur Wischnik, Ralf Witteler, Achim Wöckel, Hans-Heinrich Woeltjen, Andreas Zorr, Alessandra Bologna, Nicoletta Colombo, Germana Tognon, Saverio Cinieri, Domenica Lorusso, Anna Maria Mosconi, Sandro Pignata, Antonella Savarese, Giovanni Scambia, Roberto Sorio, Claudio Zamagni, Keiichi Fujiwara, Hiroyuki Fujiwara, Hiroaki Kobayashi, Takashi Matsumoto, Shoji Nagao, Toyomi Satoh, Kan Yonemori, Hiroyuki Yoshida, Raquel Bratos, Cristina Caballero, Yolanda Garica, Antonio González-Martín, Eva Maria Guerra Alia, Susana Hernando, Ana Herrero, Nuria Lainez, Luis Manso, Cristina Martin, Eleonor Murata, Eugenia Ortega, Isabel Palacio, Andres Poveda, Ignacio Romero, Maria Jesús Rubio, Isabelle Ray-Coquard, Eric Pujade-Lauraine, Dominique Vaur
Journal: Clinical Cancer Research (2023)

The optimal application of maintenance PARP inhibitor therapy for ovarian cancer requires accessible, robust, and rapid testing of homologous recombination deficiency (HRD). However, in many countries, access to HRD testing is problematic and the failure rate is high. We developed an academic HRD test to support treatment decision-making.Genomic Instability Scar (GIScar) was developed through targeted sequencing of a 127-gene panel to determine HRD status. GIScar was trained from a noninterventional study with 250 prospectively collected ovarian tumor samples. GIScar was validated on 469 DNA tumor samples from the PAOLA-1 trial evaluating maintenance olaparib for newly diagnosed ovarian cancer, and its predictive value was compared with Myriad Genetics MyChoice (MGMC).GIScar showed significant correlation with MGMC HRD classification (kappa statistics: 0.780). From PAOLA-1 samples, more HRD-positive tumors were identified by GIScar (258) than MGMC (242), with a lower proportion of inconclusive results (1% vs. 9%, respectively). The HRs for progression-free survival (PFS) with olaparib versus placebo were 0.45 [95% confidence interval (CI), 0.33-0.62] in GIScar-identified HRD-positive BRCA-mutated tumors, 0.50 (95% CI, 0.31-0.80) in HRD-positive BRCA-wild-type tumors, and 1.02 (95% CI, 0.74-1.40) in HRD-negative tumors. Tumors identified as HRD positive by GIScar but HRD negative by MGMC had better PFS with olaparib (HR, 0.23; 95% CI, 0.07-0.72).GIScar is a valuable diagnostic tool, reliably detecting HRD and predicting sensitivity to olaparib for ovarian cancer. GIScar showed high analytic concordance with MGMC test and fewer inconclusive results. GIScar is easily implemented into diagnostic laboratories with a rapid turnaround.